RNA疗法已经发展到药物开发的第三个里程碑,遵循化学和蛋白质疗法。RNA本身可以作为治疗剂,承运人,监管者,或药物开发中的底物。由于RNA的能动性,动态,和可变形属性,RNA纳米颗粒已证明在癌症脉管系统中自发靶向和积累,并通过肾小球快速排泄到尿液中,以防止与健康器官的可能相互作用。此外,RNA的带负电荷的磷酸主链导致带负电荷的脂质细胞膜的普遍排斥,以进一步避免重要器官。因此,RNA纳米颗粒可以自发富集肿瘤血管,通过特异性靶向有效进入肿瘤细胞,而那些没有进入肿瘤组织的人会很快从体内清除。这些有利的参数导致预期RNA具有低或小的毒性。RNA纳米颗粒的抗癌功效已得到很好的表征;然而,关于RNA纳米颗粒的病理学和安全性的细节是已知的。这里,我们报告了不同RNA纳米颗粒的病理学和安全性方面的体外和体内评估,包括带有2'-F修饰的嘧啶的RNA三通连接(3WJ),叶酸,和SurvivinsiRNA,以及带有2'-F修饰的嘧啶和24个SN38拷贝的RNA四向连接(4WJ)。研究了动物模型和患者血清。体外研究包括溶血,血小板聚集,补体激活,血浆凝固术,和干扰素诱导。体内研究包括苏木精和伊红(H&E)染色,血液和生化分析作为血清分析,和动物器官重量研究。无明显毒性,副作用,在广泛的RNA纳米颗粒安全性评估过程中检测到免疫反应。这些结果进一步补充了先前的癌症抑制研究,并证明了RNA纳米颗粒作为未来临床翻译的有效和安全的药物递送载体。
RNA therapeutics has advanced into the third milestone in pharmaceutical drug development, following chemical and protein therapeutics. RNA itself can serve as therapeutics, carriers, regulators, or substrates in drug development. Due to RNA\'s motile, dynamic, and deformable properties, RNA nanoparticles have demonstrated spontaneous targeting and accumulation in cancer vasculature and fast excretion through the kidney glomerulus to urine to prevent possible interactions with healthy organs. Furthermore, the negatively charged phosphate backbone of RNA results in general repulsion from negatively charged lipid cell membranes for further avoidance of vital organs. Thus, RNA nanoparticles can spontaneously enrich tumor vasculature and efficiently enter tumor cells via specific targeting, while those not entering the tumor tissue will clear from the body quickly. These favorable parameters have led to the expectation that RNA has low or little toxicity. RNA nanoparticles have been well characterized for their anticancer efficacy; however, little detail on RNA nanoparticle pathology and safety is known. Here, we report the in vitro and in vivo assessment of the pathology and safety aspects of different RNA nanoparticles including RNA three-way junction (3WJ) harboring 2\'-F modified pyrimidine, folic acid, and Survivin siRNA, as well as the RNA four-way junction (4WJ) harboring 2\'-F modified pyrimidine and 24 copies of SN38. Both animal models and patient serum were investigated. In vitro studies include hemolysis, platelet aggregation, complement activation, plasma coagulation, and interferon induction. In vivo studies include hematoxylin and eosin (H&E) staining, hematological and biochemical analysis as the serum profiling, and animal organ weight study. No significant toxicity, side effect, or immune responses were detected during the extensive safety evaluations of RNA nanoparticles. These results further complement previous cancer inhibition studies and demonstrate RNA nanoparticles as an effective and safe drug delivery vehicle for future clinical translations.